Comparative Study of the Effects of Cefodizime and HBW 538 in Potentiating the Production of Reactive Oxygen Species by Human Polymorphonuclear Leukocytes

Abstract

The immunomodulatory activity of cefodizime (CDZM), an aminothiazo-lylcephalosporin, was compared to that of HBW 538, a derivative of the CDZM side chain at position 3 (the mercaptothiazolyl group) in respect to the production of reactive oxygen species (ROS) by human whole blood and polymorphonuclear leukocytes (PMN) in vitro. Ten-fold diluted whole blood and PMN from healthy individuals were incubated with CDZM or HBW 538 alone at the concentrations of 1,10, or 100 μg/ml, or CDZM or HBW 538 at 100 μg/ml in combination with tumor necrosis factor-α (TNF-α) at 100 U/ml or lipopolysaccharide (LPS) at 1 μg/ml. The production of ROS was measured by a chemiluminescence (CL) assay in which luminol was added to a mixture and after which the PMN or whole blood were stimulated with nonopsonized zymosan or phorbol myristate acetate. The following results were obtained: (1) The CL responses of whole blood and PMN were slightly but not significantly enhanced by CDZM at 100 μg/ml, whereas both CL responses were significantly enhanced by exposure to HBW 538 at 10 and 100 μg/ml. (2) The enhanced PMN CL response which followed priming with TNF-α or LPS was not augmented by CDZM but was significantly augmented by HBW 538. These results indicate that the ability of the HBW 538 molecule to enhance the production of ROS by stimulated PMN and to act agonistically with TNF-α or LPS is abrogated when HBW 538 is part of the CDZM molecule. These findings have important clinical implications as they indicate that treatment with CDZM in patients with severe gram-negative septicemia would not increase tissue injury by enhancing the already excessive release of ROS by stimulated and LPS- or TNF-α-primed PMN.

Effects of Erythromycin and Rifampicin on Immunomodulatory Gene Expression and Cellular Function in Human Polymorphonuclear Leukocytes

“…Most studies have focused on the effects of antibiotics on immune cellular functions [22,23,24]. In this study, changes in the immunomodulatory gene expression in LPS-stimulated PMNs and cellular function were identified.…”